tbuckley/cabot-search huggingface dataset:
Real-world treatment trends and outcomes in elderly patients with metastatic colorectal cancer in the United States.
Authors: Andrew Trunk, Margaret Kelsey Baron, Jarrod Smith, Lisa M. Pappas, Ben Haaland, Vaia Florou, Christopher Duane Nevala-Plagemann, Ignacio Garrido-Laguna
Journal: Journal of Clinical Oncology (2023)

3591 Background: Prospective data to guide management of elderly patients with metastatic colorectal cancer (mCRC) is limited. Whether elderly patients derive the same degree of benefit from doublet chemotherapy as younger patients is not well understood. In this study we utilized real-world data from patients in the United States (US) to evaluate treatment trends and compare overall survival (OS) in younger versus older patients with mCRC who receive first-line (1L) chemotherapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was used to select patients ≥50 years old (yo) with mCRC treated with 1L fluoropyrimidine-based chemotherapy with or without the addition of targeted therapy. Overall survival from the initiation of 1L therapy, stratified by receipt of a doublet or single agent cytotoxic chemotherapy regimen was assessed independently within three age cohorts (50-69; 70-74, ≥75) using both a cox proportional hazard model and a propensity score weighted analysis to control for potential confounding variables. A subgroup analysis was performed in patients receiving bevacizumab as part of 1L therapy. Results: Of 14,440 patients who received 1L chemotherapy, 5,874 (40.7%) were ≥70 yo, including 3,656 (25.4%) who were 75 or older. Doublet chemotherapy was received by 7,505 (87.6%) patients age 50-64 yo, 1892 (85.3%) patients age 70-74 yo, and 2297 (62.2%) patients age 75 and above. In all three groups, multivariate analysis of single agent chemotherapy vs doublet chemotherapy showed a benefit to doublet chemotherapy with a hazard ratio of 1.14, (95% CI 1.04-1.24, p = 0.006), 1.22 (95% CI 1.05-1.42, p = 0.011) and 1.19 (95% CI 1.10-1.29, p &lt; 0.001), respectively. Similar results were noted when comparing doublet to single agent chemotherapy in the age 70-74 and ≥75 groups using a propensity score weighted analysis. In the subgroup of patients age ≥70 who received 1L bevacizumab, 2,604 received doublet chemotherapy and 441 received single agent chemotherapy. Median OS was 19 mos (95% CI: 18-20) vs 13 (95% CI: 11-15) vs with a propensity score weighted HR of 1.35 (95% CI 1.12-1.63, p = 0.001). Conclusions: A smaller percentage of patients over age 75 receive 1L doublet chemotherapy for mCRC in the US compared to patients age 50-69 or 70-74. Regardless of age, patients who receive doublet fluoropyrimidine-based chemotherapy appear to have improved overall survival compared to single agent chemotherapy. This retrospective US data is in contrast with recently presented data from a prospective phase III trial in Japan (JCOG1018). Elderly patients in the US should not be excluded from receiving doublet chemotherapy for mCRC without further prospective data.
Survival of de novo metastatic hormone sensitive prostate cancer in US Veterans based on treatment and PSA at diagnosis.
Authors: Arslan Babar, Robert Bruce Montgomery, Forest Riekhof, Ruth Douglas Etzioni, Nada Al masalmeh, Eric Marshall Knoche, Kristen Marie Sanfilippo, Martin W. Schoen
Journal: Journal of Clinical Oncology (2023)

e17091 Background: Combinations of androgen deprivation therapy (ADT) plus docetaxel (DOC) or androgen signaling agents (ASIs) (i.e. abiraterone, enzalutamide) improve survival in de novo metastatic hormone sensitive prostate cancer (mHSPC). In several trials, the benefit of combination therapy is greatest in patients with a high volume of disease. We sought to study the treatment and survival of US of veterans with mHSPC and stratify by PSA level at diagnosis during a time when different types of combination therapy was available. Methods: Veterans from 2018-2021 were identified with a pathologic diagnosis of prostate cancer with SEER stage ‘distant’. All veterans had ADT initiated within 1 month prior and 4 months after diagnosis. Combination therapy was determined if DOC or an ASI was initiated from 1 month prior to 4 months after ADT. Highest PSA level within 3 months of diagnosis was collected and patients with a PSA of ≥100ng/mL were included in PSA≥100. To avoid immortal time bias, all veterans had to survive 4 months after biopsy to be included. Baseline differences were compared using ANOVA and log-rank testing was used for time to event analyses. Results: 2,227 patients with de novo mHSPC were identified with mean age of 74.0 years (yrs), and 575 (25.8%) identified as Black race. From 2018 to 2021, ADT alone was used in 1,157 (52.0%) of veterans, DOC in 189 (8.4%) and ASIs in 881 (39.6%). Veterans treated with DOC were significantly younger (median 67.7 yrs, p &lt; 0.001) compared to veterans treated with ASIs (72.9 yrs) or ADT alone (75.8 yrs). Veterans treated with combination therapies had longer median OS of 40.9 months (mos) compared to 32.9 mos for ADT alone (p &lt; 0.001) with no difference within the combination treatment groups (p = 0.63). There was a trend for veterans with PSA≥100 to receive combination therapy (50.0% vs. 46.0%, p = 0.058). For 1,071 veterans with PSA≥100, median OS of veterans treated with combination therapy (n = 536, 37.4 mos) was longer than ADT alone (n = 535, 27.5 mos, p &lt; 0.001). There was no differences in DOC combination treatment (n = 100, 37.9 mos) and ASI (n = 436, 36.6 mos) treatment groups (p = 0.37). Veterans with PSA≥100 had shorter OS compared to PSA &lt; 100 (31.2 vs. 42.5 mos, p &lt; 0.001). Conclusions: In veterans with de novo mHSPC, initial combination therapy was associated with longer survival than ADT alone. There were no differences in survival between DOC and ASI combinations observed in the entire population nor in veterans with PSA≥100. Further studies including tumor genetics or response to treatment may help guide treatment in mHSPC. [Table: see text]
Impact of smoking status (SS) on the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first line (1L) immuno-oncology (IO)-combination regimens: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Georges Gebrael, Eddy Saad, Chris Labaki, Renee Maria Saliby, Nicolas Sayegh, J Connor Wells, Karl Semaan, Marc Eid, Kosuke Takemura, Matthew Scott Ernst, Audreylie Lemelin, Naveen S. Basappa, Lori Wood, Thomas Powles, D. Scott Ernst, Anil Kapoor, Wanling Xie, Neeraj Agarwal, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2023)

4555 Background: Active smoking is associated with decreased overall survival (OS) in patients (pts) with mRCC treated with VEGF targeted therapy (VEGF-TT) (Kroeger N. et al. 2019, IMDC investigators). Conversely, smoking history has been linked to improved OS in pts with advanced non-small cell lung carcinoma (NSCLC) receiving 1L pembrolizumab monotherapy (Popat S. et al., 2022). Herein, we assess the association between SS and outcomes in pts with mRCC treated with 1L standard of care (SOC) IO-based regimens. Methods: Real-world data from the IMDC were collected retrospectively. We included mRCC pts who received either dual IO therapy or IO + VEGF-TT in the 1L setting and known SS at disease diagnosis. Pts were categorized as current, former and non-smokers. The primary outcomes were OS, time to treatment failure (TTF) and objective response rate (ORR) on 1L IO-based regimens. OS and TTF were evaluated using Cox regression, adjusting for age at 1L treatment, IMDC risk groups, BMI, histological type and time from diagnosis to 1L treatment initiation. ORR was compared between the SS groups using a logistic regression, adjusting for the same confounders. Results: 989 pts were eligible and included. 438 (44.3%), 415 (42%), and 136 (13.7%) pts were non-smokers, former, and current smokers at diagnosis, respectively. Median time from diagnosis to initiation of 1L IO-based treatment was 0.47 years (IQR 0.13-2.15). At baseline, there were no significant differences in age at 1L, IMDC risk groups, KPS status, BMI, and presence of sarcomatoid features across the 3 groups (p&gt;0.05). Median follow up was 21.2 months from 1L IO-based treatment initiation. On multivariable analysis, no significant differences in OS, TTF or ORR were seen between the SS groups (p&gt;0.05). Conclusions: To our knowledge, this represents the first and largest effort to evaluate the impact of smoking on clinical outcomes in pts with mRCC treated with IO-based regimens. There was no association between SS at diagnosis and the clinical outcomes of patients with mRCC receiving current 1L SOC IO-based regimens. As opposed to other cancer types (i.e., NSCLC), current or past smoking history did not appear to be predictive of benefit from IO-based therapy. [Table: see text]
Clinical outcomes in patients with radioiodine refractory thyroid carcinoma treated with dose-reduced lenvatinib.
Authors: Cherry Au, Brian Kim, Mary Jo J. Fidler, Michael J. Jelinek
Journal: Journal of Clinical Oncology (2023)

e18104 Background: In recent years, well-differentiated thyroid cancer (WDTC) accounted for over 40,000 new cancer diagnoses annually. For patients with metastatic, iodine-131-refractory thyroid cancer, systemic therapy is sometimes warranted. Lenvatinib was FDA approved in this setting at a starting dose of 24 mg orally daily based on the SELECT trial. Many patients required dose reductions on this trial, and the use of full dose (24 mg) lenvatinib is often not feasible in clinical practice. This study characterizes the clinical outcomes of lenvatinib for WDTC in a real-world setting. Methods: This study is a retrospective chart review of all patients over 18 years old diagnosed with radioiodine refractory thyroid carcinoma who received lenvatinib at a large academic center between 05/01/2016 and 01/01/2022. Demographic information, clinical data, and treatment outcomes were obtained. Results of our study were compared to historical controls from the SELECT trial. Results: There were 38 patients included in this study. Twenty-six of 38 patients had a dose reduction prior to start of treatment per judgement of the treating physician. Of the 12 patients who started at 24 mg, 11 required a dose reduction. Starting doses of lenvatinib ranged from 4 mg to 24 mg. The mean starting dose was 17 mg. Median progression free survival and overall survival were 35.2 months and 56.2 months, respectively. Eighteen patients remain on therapy. Overall response rate was 39.5% compared to 64.8% in historical controls. Disease control rate was 63.2%. Any grade weight loss was higher in this cohort versus historical control – 92.1% vs 46.4%, respectively. Systolic ( &gt; 20 mmHg) and diastolic ( &gt; 10 mmHg) blood pressure changes occurred in 13.2% of patients. 16.7% of patients had a peak increase in creatinine &gt; 0.2 mg/dL above their baseline. Conclusions: Many patients were deemed ineligible for full dose lenvatinib by the treating physician. Despite an apparently lower response rate, lower doses of lenvatinib can still provide adequate disease control with an acceptable rate of blood pressure and serum creatinine elevation. Weight loss was an almost universal side effect of lenvatinib in this real-world population and was seen at a higher frequency than the historical population.
EO2401 (E) peptide immunotherapy + nivolumab (N) +/- bevacizumab (B) in recurrent glioblastoma (GB): EOGBM1-18/ROSALIE.
Authors: Wolfgang Wick, Ahmed Idbaih, Maria Vieito, François Ghiringhelli, Agostina Stradella, Ghazaleh Tabatabai, Michael C. Burger, Iris Mildenberger, Ulrich Herrlinger, Patrick Y. Wen, Mehdi Touat, Antje Wick, Macarena González, Alice Hervieu, Marta Gil-Martin, Mirjam Renovanz, Ana Maia, Christophe Bonny, Jan Fagerberg, David A. Reardon
Journal: Journal of Clinical Oncology (2023)

2020 Background: EO2401 was designed to activate/expand existing memory T cells recognizing specific protein sequences from gut bacteria, which cross-react with tumor associated antigens (TAAs). E contains 3 CD8 HLA-A2 epitopes with mimicry to GB-TAAs (IL13Rα2, BIRC5, and FOXM1) and the CD4 epitope UCP2. Methods: Patients (pt) at 1st progression GB received E (300 µg/peptide, q2w x4 then q4w) with N (3 mg/kg q2w) in cohorts: 1a E x2 → EN; 2a/1, 2a/2 and 2b EN from start; 2c EN x2 → surgery → EN; 3/1 and 3/2 EN + B (10mg/kg q2w) (Table). Results: Among 100 treated pt EN+/-B was well tolerated, with E associated events limited to local skin reactions (45% of pt; 96% Grades 1/2, and 4% Grade 3) and N-/B-tox consistent with historical data. EN induced immune response against all 3 mimics in 94% of 35 tested pt (all pt responded against at least 2 mimics), detectable as early as 2 weeks after first EN, and with durations beyond 10 months. Cross-reactivity against human peptides found in 89%. Conclusions: EN +/- B was well tolerated and generated fast and durable immune responses. EN survival like current standards. Delayed N was not advantageous for outcome. sLDB increased trt duration of EN, and improved efficacy. Continuous B plus EN further improved efficacy. Neo-/adjuvant EN was clinically feasible. Updated data, including C3/2 to confirm C3/1, to be presented. Clinical trial information: NCT04116658 . [Table: see text]
Androgen receptor inhibitors and anti-NKG2A checkpoint inhibitor to enhance NK cell–mediated killing of prostate cancer cell lines in vitro.
Authors: Maximilian Schwermann, Vida Tajiknia, Lanlan Zhou, Andrew George, Praveen Srinivasan, Andre De Souza, Anthony E. Mega, Howard Safran, Benedito A. Carneiro, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2023)

e17066 Background: The blockade of the androgen receptor (AR) pathway is essential for the treatment of prostate cancer (PC). Checkpoint inhibitors have limited activity in immunologically cold prostate tumors. Emerging results suggest that AR signaling modulates CD8+ T cells and modifies its cytotoxic function, but the therapeutic role of NK cells in anti-tumor immune response in PC remains unknown. We investigated the mechanisms of AR inhibitors (ARi) enzalutamide (Enza) and darolutamide (Daro) on the antitumor function of NK cells and their enhancement when combined with NKG2A inhibitor. Methods: We performed co-culture assays with PC cell lines (LNCap, 22Rv1 [ARv7 mutation], DU145, PC3 [AR-]) and NK-92 cells, in a 1:1 ratio, in the presence of ARi and in combination with the anti-NKG2A mAb monalizumab and analyzed immune cell-mediated tumor cell killing (ImageXpress Confocal HT). NK cells expression of NKG2A and PD-1 receptors and PC cell lines expression of HLA-E and PD-L1 were investigated after treatment with Enza and Daro by flow cytometry. Results: ARi significantly increased immune-mediated NK-92 cell killing of PC cell lines at 24hrs (control[C]: 15.8%±3.9; Enza: 40%±4.3; Daro: 36%±3.72, p &lt; 0.0001). This immune enhancement effect was increased by NKG2A blockade with monalizumab ([C]: 31.2%±3.1, [T]: 43.92%±4.52, p = 0.0045). Treatment of the LNCaP cell line (AR+) with ARi increased HLA-E ([MFI values x10³] control[C]: 28.57±2.9; [T]: 37.38 ±1.2 p = 0.0046) and PD-L1 expression ([MFI values x10³] control[C]: 163.1±8.1; [T]: 202.5±11.2 p = 0.003). No significant difference was observed in the surface expression of these markers in the AR- cell lines. NKG2A surface expression on NK cells was also upregulated upon treatment with ARi ([MFI values x10³] control[C]: 52.42±2.9; [T]: 61.4 ±2.2 p = 0.008). Conclusions: Enza and Daro enhance NK cell killing of PC cell lines, and the combination of ARi with checkpoint inhibitor monalizumab promotes NK cell activation. Blockade of AR signaling modulates PC cells' expression of HLA-E and PD-L1 and NK cell expression of NKG2A. These results describe a novel modulatory effect of androgen on NK cell function and provide insights for future NK-cell-based therapeutic approaches for treating PC. Experiments validating these results in patient samples are ongoing.
Impact of overfixation on actionable biomarkers and checkpoint inhibitor (CKI) targets with immunohistochemistry (IHC) in a patient population with non-small cell lung cancer (NSCLC).
Authors: Marie Gérus-Durand, Rania Gaspo, Ming Sound Tsao, Alexandra Jean, Jérôme Sallette, Renaud Burrer, Amanda Finan
Journal: Journal of Clinical Oncology (2023)

e15144 Background: The treatment of patients with advanced NSCLC has become reliant on tissue specimens and biomarkers to help guide appropriate treatment options. Currently, there are numerous lung cancer biomarker-defined patient subgroups, with evidence showing that fixation conditions may alter their expression on FFPE specimens, but little evidence on the ensemble of targetable biomarkers and CKI targets. Methods: We assessed 30 adult patients with primary NSCLC tumors. 25 specimens were properly fixed with neutral 10% formalin using gentle agitation for 24-48 hours, whereas 5 specimens were over-fixed (52-108 hours). We examined expression of actionable and exploratory biomarkers ALK, ROS1, BRAF, EGFR, c-Met, panTRK, HER2 and MEK1. We also examined CKI targets such as PDL1, CD3/CD8, CD3/CD8/FoxP3, PD1, CD3/CD8/PD1. We performed IHC on all slides which were scored by a thoracic pathologist per standard clinical practice. Descriptive statistics were applied to further explore the impact of overfixation on IHC results. Results: Results are shown in the table below. Patients had an average age of 64, were mostly male (22/30) with adenocarcinoma histology (21/30). Specimens were collected in compliance with local rules and regulations and tumor staging was from IB-IV. For the 5 overfixed specimens, multiplex PD-L1 was less expressed when compared to the normally fixed specimens. We also surprisingly observed that cMet and HER2 had stronger expression with overfixed tissue. All other targets had no differences observed in this small patient population. Conclusions: Overfixation of NSCLC FFPE had little to no detrimental impact on most targetable biomarkers, except multiplex PD-L1. We also observed that cMet and HER2 had a slightly stronger expression level with overfixed tissue. As we do not have a reference of the overfixed samples fixed from 24-48 hrs, we cannot be assured that the differences in expression levels are not inherent to the sample itself and independent of fixation time. Additional tests of the same sample fixed over different periods will help to identify the true cause. We propose a consistent approach on tissue fixation time and process as the ensemble of preanalytical conditions is critical in ensuring proper biomarker characterization and validation with IHC. [Table: see text]
Longitudinal transcriptome profiling of localized hormone-sensitive tumors in treatment-naïve ENACT patients with prostate cancer with and without enzalutamide (ENZA).
Authors: Ashley Ross, Neal D. Shore, Elai Davicioni, Xin Zhao, Dina Elsouda, Yang Liu, James A. Proudfoot, John Hairston, David Russell, Kenneth K. Iwata, Edward M. Schaeffer
Journal: Journal of Clinical Oncology (2023)

5026 Background: The ENACT trial (NCT02799745) randomized men with low- or intermediate-risk prostate cancer to 12 months of ENZA monotherapy followed by active surveillance (AS) for 12 months or to AS alone. Men were followed longitudinally, including by serial genome-wide expression profiling. Of 258 genomic signatures evaluated from baseline samples, increased Decipher genomic classifier score was prognostic for progression on AS; androgen receptor activity (AR-A) and PAM50 subtypes were associated with clinical benefit from ENZA, as previously reported. Here we present transcriptomic changes over time for men undergoing AS and those treated transiently with ENZA. Methods: Gene-expression profiling was performed via the Decipher GRID platform (Veracyte, Inc.) on 131 ENACT patient samples (ENZA, n=57; AS, n=74) collected at prespecified time points (screening, 12 months, and 24 months). Predefined GRID signatures were assessed for correlation with biological and clinical characteristics, including immune activity, treatment sensitivity, metastatic risk, and molecular subtypes. Statistical analysis was conducted by Cox proportional hazards models and logistic/linear regression; longitudinal changes were assessed by linear mixed-effects models. Results: Analysis of 12-month longitudinal samples showed significant transcriptomic changes in patients treated with ENZA, including markers of AR-A downregulation, decreased regulatory T-cell suppression, and increased immune activation. Many of the transcriptomic signature changes that occurred during ENZA treatment, including immune marker changes, were transient and returned to baseline values by 24 months following ENZA treatment discontinuation at 12 months. Conclusions: This exploratory biomarker analysis provides valuable data on transcriptomic changes in patients undergoing AS and those exposed to ENZA followed by cessation of treatment. Longitudinal analysis data provided insights into progression of early disease in the AS arm and possible strategies for extending ENZA activity beyond progression. Immune modulation with ENZA treatment may provide further insights for exploration of immunotherapy strategies. Clinical trial information: NCT02799745 .
VIC regimen (vemurafenib/irinotecan/cetuximab) versus bevacizumab plus chemotherapy as first-line treatment for <i>BRAF</i> <i>V600E</i>-mutated advanced colorectal cancer.
Authors: Yijiao Chen, Dexiang Zhu, Ye Wei, Jianmin Xu
Journal: Journal of Clinical Oncology (2023)

3596 Background: The need for safe and effective therapies for untreated, BRAF V600E-mutated, unresectable locally advanced or metastatic colorectal cancer remains unmet. The purpose of this study was to compare the efficacy and safety of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen versus bevacizumab plus chemotherapy as first-line setting in Asian patients. Methods: In the single-center prospective cohort study, 78 untreated, BRAF V600E-mutant, locally advanced or metastatic CRC patients were enrolled. Every two weeks, the VIC regimen and bevacizumab plus doublet or triplet chemotherapy are administered. We evaluated the objective response rate (ORR), the disease control rate (DCR), and the conversion resection rate. In progression-free survival (PFS) and overall survival, the Kaplan-Meier method was utilized (OS). Results: In the evaluable population, 32 patients received VIC regimen and 35 patients received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 68.8% versus 40.0%, P = 0.018; DCR: 100.0% versus 80.0%, P = 0.023). The VIC regimen was significantly superior to bevacizumab plus chemotherapy for PFS (median, 11.9 vs 7.9 months; hazard ratio [HR] = 0.48, 95% CI, 0.27-0.87; P = 0.012) and OS (median, 24.5 vs 14.4 months; HR = 0.36, 95% CI, 0.16-0.78; P = 0.007). In the VIC group, the conversion resection rate for liver metastases was 42.1% (8 of 19 patients), and for local CRC it was 66.7% (6 of 9 patients with initially unresectable local CRC). Rates of treatment-related adverse events of Grade 3 to 4 were 32.4% and 31.1% for the VIC regimen and bevacizumab plus chemotherapy, respectively. Conclusions: Among Asian patients with BRAF V600E-mutated advanced CRC, the VIC regimen was superior to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting. Clinical trial information: NCT05540951 .